title: Renoprotection with pituitary adenylate cyclase-activating polypeptide in cyclosporine A-induced nephrotoxicity.
abstract: BACKGROUND
  Acute and long-term nephrotoxicity is the major dose-limiting factor for cyclosporine A (CsA). We evaluated the protective effects of pituitary adenylate cyclase-activating polypeptide (PACAP)38 on CsA-induced nephrotoxicity in human renal proximal tubule epithelial (human kidney-2) cells and in intact mice.
  
  
  METHODS
  Confluent (human kidney-2 cells were exposed to CsA (25-50 μmol/L) in the presence or absence of PACAP38 or vasoactive intestinal peptide (10(-10) to 10(-6) M). For studies in vivo, male BALB/c mice (n = 5 in each group) were given a single intraperitoneal injection of CsA (5 mg/kg body weight). Treatment group received 20 μg of PACAP38 2 hours before exposure to CsA and additional doses daily for 10 days.
  
  
  RESULTS
  Cyclosporine A caused oxidative injury, marked morphological alterations, apoptosis, and increased expression of transforming growth factor (TGF)-β1 in cell cultures. Pituitary adenylate cyclase-activating polypeptide 38 at 10(-8) mol/L restored cell confluency, reduced TGF-β1 secretion, and preserved cell integrity. In mice, CsA caused tubular injury characterized by loss of tubular epithelial cell brush border membranes, tubular collapse, cellular necrosis, interstitial fibrosis, increased production of TGF-β1, and elevated serum creatinine (3.39 ± 0.21 vs 0.13 ± 0.02 mg/dL in controls, P < 0.01). Treatment with PACAP38 reduced TGF-β1 and tumor necrosis factor-α production in kidney, prevented epithelial-mesenchymal transition of the renal cells, and reduced serum creatinine levels to 1.01 ± 0.18 mg/dL, P < 0.01 versus CsA group.
  
  
  CONCLUSIONS
  Pituitary adenylate cyclase-activating polypeptide 38 ameliorated renal tubular injury, reduced oxidative injury, and inhibited the expression of TGF-β1 in CsA-exposed murine kidneys. Pituitary adenylate cyclase-activating polypeptide could be a novel renoprotective and antifibrotic agent for CsA nephrotoxicity.
authors.affiliation: Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112-2632, USA.
authors.forename: Altaf-M
authors.initials: AM
authors.lastname: Khan
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Brant
authors.forename: Jerome L
authors.initials: JL
authors.lastname: Maderdrut
authors.forename: Dewan S A
authors.initials: DS
authors.lastname: Majid
authors.forename: Eric E
authors.initials: EE
authors.lastname: Simon
authors.forename: Vecihi
authors.initials: V
authors.lastname: Batuman
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016572:Cyclosporine